1. Strategic Timing of Antiretroviral Treatment Washington International Coordinating Center (DC ICC) IMPAACT Site Training 7 June 2011

2. Strategic Timing of Antiretroviral Treatment STUDY RATIONALE

3. Pantaleo G, et al. N Engl J Med 1993 The Natural History of HIV Infection

4. Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases

5. Unexpected results from SMART led to a new way of thinking about non-AIDS events. The findings from SMART motivate START.

6. SMART: Severe Complications Endpoint and Components No. of Patients with Events Subgroups Severe Complications 114 Non-Fatal CVD Events 63 Non-Fatal Hepatic Events 14 Non-Fatal Renal Events 7 Favors VS ► Relative Risk (95% CI) 1.5 1.5 1.4 2.5 1.4 CVD, Liver, or Renal Deaths 31 > ► Favors DC

7. Selected Publications on Non-AIDS Events

8. Evolution of Focus of Concern Opportunistic infections & malignancies CMV PCP MAC Toxoplasmosis Cryptococcosis Candidiasis Histoplasmosis Kaposi Sarcoma Complications of therapy CVD Metabolic Renal Hepatic Neurologic Hematologic Serious, non-AIDS morbidities MI Stroke Renal Failure Hepatic Failure Malignancies Time

9. Natural History of Untreated HIV-1 Infection Revisited Clinical Latency Time in Years Infection CD4 Cells 1000 800 600 400 200 0 Early Opportunistic Infections Late Opportunistic Infections + 1 2 3 4 5 6 7 8 9 10 11 12 13 14

10. A New Paradigm: Time in Years Infection CD4+ cells 1000 800 600 400 200 0 Early Opportunistic Infections Late Opportunistic Infections 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Ongoing Morbidity from HIV The Broader Spectrum of HIV Disease

11. Can Anything be Done? Ongoing Morbidity from HIV Time in Years Infection CD4 Cells 1000 800 600 400 200 0 Early Opportunistic Infections Late Opportunistic Infections + 1 2 3 4 5 6 7 8 9 10 11 12 13 14

12. SMART subset analyses A subset of SMART participants not on ART at baseline were examined; this analysis further informed the design of START Drug Conservation (DC) Strategy Virologic Suppression (VS) Strategy Patients not on ART at baseline (n=477) Immediate ART (n=249) Deferred ART until CD4+ < 250 (n=228)

14. Would Earlier ART Prevent Morbidity and Mortality in HIV?

15. Shifting recommendations for “When to start ART” – IAS USA panel, 1996-2010 > 500 VL>5K VL>10K 350-500 VL>5K VL>5K 200-350 <200 CD4 1996 1998 2000 2002 2004 2006 2008 2010

16. When to start ART? Summary of Current Guidelines For asymptomatic patients CD4 <350 CD4 350-500 CD4 >500 EACS, 2009 treat defer W/ SPECIAL CONSIDERATIONS defer US DHHS, 2011 treat treat No consensus WHO 2010 treat --- ---

22. Strategic Timing of Antiretroviral Treatment PROTOCOL OVERVIEW

23. START Design HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 Early ART Group Initiate ART immediately following randomization N=2,000 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,000

36. Initial ART Regimens in START To Construct an Antiretroviral Regimen, Select 1 Component from Column A + 1 from Column B Column A (NNRTI or PI or Integrase Inhibitor Options) + Column B (Dual-NRTI Options) NNRTI PI efavirenz OR atazanavir + ritonavir (1x/day) darunavir + ritonavir (1x/day) fosamprenavir + ritonavir (2x/day) fosamprenavir + ritonavir (1x/day) lopinavir/ritonavir (2x/day) lopinavir/ritonavir (1x/day) OR Integrase Inhibitor (II) raltegravir (2x/day) abacavir/lamivudine tenofovir/emtricitabine zidovudine/lamivudine

37. Strategic Timing of Antiretroviral Treatment STUDY FUNDING & ORGANIZATION

51. Strategic Timing of Antiretroviral Treatment ACCRUAL & BASELINE CHARACTERISTICS

52. START: Where are we now? As of 31 May 2011 ICC Sites Sites Registered Sites open N Participants Copenhagen 58 33 29 399 London 49 27 24 239 Sydney 48 22 17 224 Washington 80 43 39 445 Total 236 125 109 1307

53. Enrollment by Month 31 May CDR opens

54. Enrollment by Country Country N (%) Country N (%) USA 192 (15) Australia 45 (4) Germany 185 (15) Poland 39 (3) Brazil 96 (7) Chile 39 (3) Spain 81 (6) Greece 27 (2) France 77 (6) Mali 24 (2) UK 77 (6) Denmark 23 (2) Argentina 70 (5) Morocco 22 (2) South Africa 61 (5) Switzerland 18 (1) Thailand 59 (5) Finland 15 (1) Belgium 54 (4) Italy 11 (1) Peru 54 (4) Israel 10 (1)

55. Demographics Median Age (years, IQR) 36 [29, 44] Gender (% female) 16 Race (%) Asian 6 Black 17 Latino/Hispanic 14 White 61 Other 2

56. Age Distribution Percent Age Group

57. START Baseline CD4 Distribution Percent (%) CD4 Cell Count (cells/mm 3 ) Median (IQR) 634 (577 - 720) Sample size assumptions: 501-600 70% 601-700 20% > 700 10%

58. Baseline CD4 Distribution Percent (%) CD4 Cell Count (cells/mm 3 ) Median (IQR) 634 (576 - 726)

59. Baseline HIV-RNA Distribution Percent (%) HIV-RNA Level (copies/mL) Median (IQR) 14,090 (3,789 – 43,889)

60. Percent with Clinically Elevated Modifiable CVD Risk Factors, by Region Percent (%)

61. % of Participants With Favorable* CVD Risk Factor Profile * Age (years) < 30 31-40 41-50 > 50 Men 25% 16% 9% 12% (N=245) (N=278) (N=237) (N=82) Women 36% 33% 10% 8% (N=53) (N=43) (N=41) (N=26) cholesterol < 200 mg/dL SBP < 120 DBP < 80 non-smoker no diabetes no prior CVD

62. Follow-up Completeness Visit No. Expected Percent Completed Month 1 1148 97 Month 4 960 97 Month 8 634 94 Month 12 265 93 Month 16 91 94 Month 20 37 100 Month 24 5 100 Overall 3140 96